This invention relates to benzylamines and processes for their preparation, pharmaceutical compositions containing them and pharmaceutical methods using them. These compounds have shown activity as inhibitors of the enzyme phospholipase A.sub.2.
The important role of phospholipase A.sub.2 in the biosynthesis of prostaglandins and leukotrienes indicates that inhibitors of phospholipase A.sub.2 may be valuable therapeutic agents having wide applicability in inflammatory and/or allergic conditions in mammals. Although some currently-available anti-inflammatory agents show activity against phospholipase A.sub.2 or other enzymes of the "arachidonic acid cascade", there is a continuing need for safer and more effective drugs capable of treating inflammatory and/or allergic diseases.
U.S. Pat. No. 4,239,780 (issued to D. P. Wallach on Dec. 16, 1980) discloses the use for treating phospholipase A.sub.2 mediated conditions of compounds of the formula: ##STR1## wherein R.sub.1 is 4-Cl, 4-CF.sub.3, H, or 2- or 4-CH.sub.3 ;
R.sub.2 is CH.sub.3 --O--, --CH.sub.2 --OH, or H; PA1 R.sub.3 is H or CH.sub.3 ; and PA1 R.sub.4 is F or Cl. PA1 n is 1 to 5; PA1 X is NH, S(O).sub.p, or O; p is 0, 1, or 2; and PA1 R is C.sub.7-20 alkyl, pyridyl, or a mono- or polycyclic benzoid aromatic system of the formula: ##STR4## where W is C.sub.1-20 alkyl, F, Cl, Br, --OR.sup.2, --S(O).sub.q R.sup.2, --C(CF.sub.3).sub.2 OH, or phenyl, and R.sup.2 is methyl or ethyl, and q is 0, 1, or 2; or PA1 R is benzhydryl, phenyl-(4-pyridyl)methyl, alkaryl or substituted alkaryl of 7 to 25 carbon atoms where the substitution is on the aromatic moiety, and is F, Cl, Br, OR.sup.3, S(O).sub.r R.sup.3, or C.sub.1-10 alkyl, where R.sup.3 is methyl or ethyl, and r is 0, 1, or 2; PA1 a. when Z is H, X is NH, and n is 2, then R cannot be benzhydryl; PA1 b. when X is NH, then R cannot be phenyl or benzyl; PA1 c. when X is S, W cannot be OCH.sub.3 ; and PA1 d. when X is O, n cannot be 2. PA1 Ar is ##STR5## and Z is H, F, Cl, Br, --OCH.sub.3, or S(O).sub.m CH.sub.3 where m is 0, 1, or 2; PA1 n is 1, 2, or 3; PA1 X is NH or S. PA1 Ar is ##STR6## where Z is H, F, Cl, OCH.sub.3, or SCH.sub.3 ; n is 2 or 3; PA1 X is NH or S; and PA1 R is C.sub.10-12 alkyl, or ##STR7## where W is C.sub.1-12 alkyl; or R is alkaryl or substituted alkaryl of 7 to 25 carbon atoms, where the substitution is on the aryl moiety and is OCH.sub.3, SCH.sub.3, F, Cl, or C.sub.1-10 alkyl.
These compounds and their activities as inhibitors of phospholipase A.sub.2 are also described in D. P. Wallach and V. J. R. Brown, Biochemical Pharmacology, 30, 1315 (1981).